Results provide evidence for the importance of Cernunnos/XLF in DSB repair, maintenance of genomic stability and survival under replication stress conditions. Hence, we conclude that Cernunnos/ XLF mutations in immunodeficiency patients disrupt the ability of cells to respond appropriately to replication stress conditions and therefore may jeopardize the cells when they are hyperproliferating during embryonic development or in early stages of tumor development.The mutant mice have fewer mature B cells in the BM and spleen and mount sub-optimal TD-antigen responses. Additionally, baseline IgM production as well as T cellindependent antigen-specific IgM production is severely impaired, most likely as a result of the complete absence of CD5 + B-1 cells in the peritoneal cavity. Our findings suggest novel functions for TRAF6, which appears to be required for both B-1 and B-2 cell homeostasis and to play a role in both in TI and TD humoral immune responses. MLN4924 side effects atherosclerosis is the primary cause of coronary artery disease , one of the most common causes of illness and death worldwide. There is increasing recognition that lesion composition rather than size determines the acute complications of atherosclerotic disease in humans. Several studies suggested that thin-cap fibroatheroma are prone to rupture and result in acute coronary artery occlusions , whereas obstructive, calcified plaques result in clinically stable angina pectoris. Initiation and progression of the atherosclerotic lesion are highly complex processes, and many aspects of atherogenesis remain incompletely understood. Ectopic visceral adipose tissue was linked to the pathogenesis of atherosclerosis due to secretion of a multitude of pro- and anti-atherogenic cytokines and adipokines. This effect of Cernunnos/XLF mutation on the stability of fragile sites was not the result of perturbed replication progression as shown in Figure 6. Several patients have been described in the literature harboring mutations in the NHEJ factors Ligase IV, Artemis or Cernunnos/ XLF. In the majority of the patients, mutations in any of these genes leads to immunodeficiency, indicating the immediate effect of mutations in NHEJ on VJ recombination. In many of the cases, including those harboring mutations in Cernunnos/ XLF, patients are born with developmental anomalies, such as microcephaly and growth retardation, and show chromosomal instability. These phenotypes are probably not related to the VJ recombination defect in the immune system, but rather likely result from a general inability to repair spontaneous DSBs occurring during embryonic development throughout the body. One major source of spontaneous DSBs is the DNA replication process. Indeed cells carrying mutations in DNA-PK were shown to be deficient in repair of replication-induced DSBs. Our results provide the first evidence that a disease caused by mutations in NHEJ genes is associated with defective response to conditions which perturb DNA replication.